9alpha-alkyl steroids and their method of preparation



United States Patent 9oz-ALKYL STEROIDS AND THEIR METHOD OF PREPARATION Gordon H. Thomas, New Brunswick, and Josef Fried, Princeton, N.J., assignors to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Filed Nov. 18, 1957, Ser. No. 696,903 7 16 Claims. (Cl. 260-23955) This invention relates to the synthesis of steroids, and has for its object the provision of a new class of physiologically active steroids, which may be represented by the formula wherein the 1,2-position is saturated or double-bonded, R is hydrogen, R is a-hYdIOXLo-aCYIOXY, or fi-hydroxy, or together R and R is'keto, R"-is"1'ower alkyl (preferably 9a-fluoro-ll-ketoprogesterone; 9a-fluoro-A -pregnadiene- 3,11,20-trione; 9u-fluorocortisone or a 21-ester thereof; 9a-fluoro-prednisone or a 21-ester thereof; 9a-flu0r0-11- keto-l7u-hydroxy-progesterone; 9a-fluoro-A -pregnadiene-17a-ol-3,l 1,20-trione; 9cz-fll1OIO-1 l-dehydrocorticosterone or a 2l-e'ster thereof; and 9a-fluoro-A -pregnadiene-2l-ol-3,ll,20-trione or a 2l-ester thereof; thereby yielding the corresponding 3,20-diketal wherein the9a fluoro radical is replaced with a lower alkyl group. The resulting diketal can then be hydrolyzed in the usual manner to give the free 3,11,20-triketone; or reduced to yield the corresponding ll-hydroxy derivatives. If the reduction is carried out with a reducing agent such as lithium aluminum hydride, the llfi-hydroxy derivative is obtained as the major product. If, on the other hand, the reduction is done by means of a reducing agent such as lithium metal in liquid ammonia, the lla-hydroxy derivative is recovered. Both of these ll-hydroxy derivatives can then be hydrolyzed in the usual manner to yield the respective 3,20-diketone derivatives. The resulting 9ozmethyl-llu-hydroxy steroids can. then, if desired, be acylated in the usual manner, as by treatment with the acid anhydride or acyl halide of the desired acid, to 'yield the corresponding lla-acyloxy derivative. g This series of steps is illustrated by the following equations. wherein the 3,20-bis-ethylene ketals of 9a-fiuorocortisone, and ,9u-fluoro-1l-ketoprogesterone are employed as starting materials: a g t CHiY' CHzY .As suitable starting materials for the process of this invention may be mentioned any 3,20-diketa1 of the steroids listed hereinbefore, as-exemplified by the diketals with 1,2 or 1,3-dihydric alcohols such as ethylene glycol and propylene glycol. These diketals are then reacted with an organometal. If a Grignard reagent (i.e. a lower'alkyl magnesium halide), such as methyl magnesium bromide or iodide or ethyl magnesium bromide or iodide, is employed as the reactant, thenin all instances a Qua-lower alkyl derivative is obtained. If, however, a lithium lower alkyl is used as the alkylating agent and the steroid reactant is a progesterone (Y. and Z are hydrogen), a l2a-lower alkyl derivative is obtained. In all but the progesterone series (i.e. Y or Z .or both are hydroxy or acyloxy), however, a lithium lower alkyl .(e.g. lithium methyl) also yields a 9ot-lower akyl derivative. In either event the reaction is preferably conducted in an inert organic solvent for the steroid at any normal temperature, such as ambient temperature. The reaction results in a mixture of two products, one of which is the desired 3,20-diketal of the 9a-methyl-ll-keto steroid, and the other is the 3,20-diketal of the Ila-methyl- 9fi,11B-oxido steroid. The products eanbe separated by fractional crystallization. v The 9u-methyl ll-keto steroid diketas formed can then be hydrolyzed in the usual manner, as by treatment with a dilute aqueous acid at'an elevated temperature, to yield the corresponding 3,11,20-triketone derivatives.

The 9a-methyl-1l-keto steroid diketals can alsobe reduced to the corresponding ll-hvdroxv derivatives. If this reduction is done by means of lithium aluminum hydride. preferably at an elevated temperature with the steroid-reactant in solution. the corresponding llfi-hydroxy derivative is obtained as the major product. If,

however, the reduction is carried out by means of an.

alkali metal (eg. lithium) in liquid ammonia, then the lla-hydroxy derivatives are formed.

In either event the ll-hvdroxv steroid obtainedcan then he h drolyzed as described hereinbefore to the free 3,20-diketone.

The lla-hydroxy derivatives can further be acylated in the usual manner by treatment with an acvl halide or acid anhydride of the desired acid. Particularly preferred are the acvl chlorides or acid anh drides of hvdrocarbon carboxylic acids having less than ten carbon atoms, as exemplified by the lower alkanoic acids (e.g. acetic, propionic. and enanthic acid), the mouocyc ic aromatic carboxylic acids (e.g., benzoic and toluic acid), the monocyclic aralkanoic acids (eg. phenacetic and fl-phenvlpropionic acid), the lower alkenoic acids, the

cycloalkane carboxylic acids, and the cvcloalkene carboxylic acids. The acylation is preferably conducted in the presence of an or anic base. such as p ridine.

Furthermore, if a free ZI-hvdroxv steroid is obtained, it may be converted to a ZI-ester derivative by acylation in the usual manner. as described hereinbefore.

The steroids of this invention wherein free keto groups are present in the 3 and positions are physiologically active substances which possess anti-inflammatory ac- X=CH=CO; z=cmcoo tivity. Hence, the steroids of this invention can be used in lieu of known anti-inflammatory steroids, such as hydrocortisone, in the treatment of rheumatoid arthritis, being formulated for such administration in the same type of peroral preparations, with concentration and/or dosage based on the activity of the particular compound.

The following examples are illustrative of the invention (all temperatures being in centigrade):

EXAMPLE 1 Qa-methyHI-ket0pr0gesterone 3,20-bis-ethylene ketal (I) A solution of 1.3 g. of 9a-fluoro-1l-ketoprogesterone- 3,20-bis-ethylene ketal in 130 ml. of other is treated with 20 ml. of ethereal methyl magnesium bromide (prepared from 1.3 g. of magnesium and 2.6 ml. of methyl bromide). The solution is stirred for 16 hours at room temperature and then the excess Grignard reagent is decomposed by the addition of ice. Ether (300 ml.) is added and the organic solution is washed with 5% aqueous ammonium chloride and then with water. The dried ether solution is evaporated under reduced pressure to give about 1.1 g. of residue which is taken up in 60ml. of hexane-benzene (1:2,) and absorbed on 30 g. of alumina. iElution with benzene (500 m1.) and with chloroform-benzene (1:99, 200 1111.), followed by three crystallizations from acetone-hexane gives about 30 mg. of llu-methyl-9,8,11fioxidoprogesterone-3,20-bisethylene ketal, M.P. about 191-193". :Elution of the column with chloroformbenzene (1:9, 'ZOOmL; 1:4, 200 ml.) followed by crystallization from acetone-hexane gives about 20 mg. of 9u-methyl-ll-ketoprogesterone-3,ZO-bisethylene ketal (I), having melting point 200-204, [a] +12.2 (c. 0.94 in C HCl -.Analysis.Calcd. for .C H O (430.56): C, 72.52; H, 8.90. Found: C, 72.60; H, 8.88.

Similarly, if ethyl magnesium bromide is substituted for the methyl magnesium bromide in Example 1, 9a-ethylll-ketoprogesterone 3,20-bis-ethylene ketal (II) is obtained.

EXAMPLE 2 Qa-methyl-l 1 -ketoprogesterone 3,20-bis-ethylene ketal (I) and 9a-methyl-1I-ketoprogesterone (IV) 10 g. of 9a-fluoro-1l-ketoprogesterone 3,20-bis-ethylene ketal in 200 ml. of benzene is treated with ml. of an ethereal solution of methyl magnesium bromide (prepared from 5 g. of magnesium and 10 ml. of methyl bromide), the solution then being stirred at room temperature overnight. The steroids are isolated with chloroform as described in Example 1, and the resultant product is hydrolyzed by heating in 40 ml. of methanol and 4 ml. of 8% sulfuric acid for 4 hours. Isolation with chloroform followed by trituration of the residue with methanol yields about 260 mg. of the 9m-methyl-1l-ketoprogesterone 3,20-bis-ethylene ketal (I) having melting point .H, 8.28,. Found: .C, 67.41; H, 8.19.

an analytical sample of this steroid having M.P. 178- 180; [eth l-105 (c. 0.98 in CHCl Ag? 241 (12,600); A232 5.86, 6.00, 6.23;

Analysis.Calcd. for C H O (342.46); C, 77.15; H, 8.83. Found: C, 77.11; H, 8.67.

Elution of the column with chloroform-benzene (1:4, 1 1.; 1:1, 1 1.) followed by two crystallizations from acetone-hexane yields about 165 mg. of the 9a-methylll-ketoprogesterone (IV), melting at about 210.215.

EXAMPLE 3 9a-methyl-1I-ketoprogesterone (IV) To a solution of 2 g. of 9a-fll101O-l l-ketoprogesterone- 3,20-bis-ethylene ketal in 50 ml. of benzene is added ml. of an ethereal solution of methyl magnesium bromide (prepared from 1 g. of magnesium and 2 ml. of methyl bromide in 20 ml. of ether) and the solution is stirred at room temperature for 18 hours. The excess Grignard reagent is then decomposed by the careful addition of ice. Chloroform (200 ml.) is added, and the mixture is washed several times with 5% ammonium chloride solution followed by water, and then dried and evaporated in vacuo. A solution of the residue in 50 ml. of methanol and 5 ml. of 8% sulfuric acid is heated under reflux for 4 hours. The mixture is diluted with water and the steroids extracted with chloroform, the chloroform extract then being washed well with water, dried over sodium sulfate and evaporated to dryness in vacuo. Trituration of the residue with ice-cold methanolyields about 215 mg. of 9a-methyl-ll-ketoprogesterone (IV), having melting point about 211-218. Crystallization from chloroformmethanol yields an analytical sample having melting point about 222-224"; [a] +305 (c. 0.94 in CHCl A22, 238 m (18,500); A222 5.87; 5.99; 6.1814

Analysis.--Calcd. for C H O (342.46): C, 77.l5; H, 8.83. Found: C, 77.24; H,-8.66.

EXAMPLE 4 9u-methylcortisone 3,20-bis-ethylene ketal (III) To a solution of 600 mg. of 9a-flu0rocortisone-3,20- bis-ethylene ketal in 130 ml. of benzene is added 'with stirring under nitrogen, 8 ml. of 2.5 molar solution of methyl magnesium bromide in ether (prepared from 1.2 g. of magnesium and 3 ml. of methyl bromide in 20 ml.

of ether). The reaction is permitted to proceed for 3 'bisethylene'ketal (about 206 mg.) which upon recrystallization from the same solvent furnishes the pure com- 7 pound, having the following properties: M.P. about 221- +2 (c. 1.3 in chlf.);

max.

Analysis.'-Calcd. for c2 H33O7 (462.56): C, 67.51;

6 EXAMPLE 5- 9a-r nethylc0rtis0ne 3,20-liis-ethylene ketal (III) and Ila mezhyl 9/3,] 1 B-oxido-M-pregnene-l7,21-di0l-3,20-di0ne 3,20-bis-ethylene ketal.

To an ethereal solution of methyl lithium (prepared from 2.64 g. of lithium and 11 ml. of methyl bromide in 200 ml. of ether) is added 5.51 g. of 9a-fluorocortisone- 3,20-bis-ethylene ketal in 1,200 ml. of benzene. .The resulting solution is stirred at room temperature for three hours with the exclusion of air. Excess methyl lithium is decomposed by the cautious addition of ice and the benzene layer separated from the aqueous phase. The benzene extract is washed neutral with water, dried over sodium sulfate and evaporated to dryness in vacuo. The amorphous residue crystallizes readily upon addition of methanol. The first crop after 2 recrystaliizations from methanol furnishes pure Ila-methyl 9 3,11 )3 oxido A pregnene-17u,21-diol-3,20-bis-ethylene ketal (about 550 mg.) of the following properties: M.P. about 199-200; [a] -|66 (c. 1.0 in chlf.);

Analysis.-Calcd. for C H O (462.56): C, 67.51; H, 8.28. Found: C, 67.27; H, 8.23.

Concentration of the mother liquors yields in three consecutive crops material melting at about 218-222 which isidentical in all respects with 9a-methylcortisone- 3,20-bis-ethylene ketal.

Similarly, by the following the procedure of the foregoing examples, but substituting one of the following: 9a-fluoro-1l-dehydrocorticosterone 3,20-bis-ethylene ketal; 9a-fluoro-1l-keto-17a-hydroxyprogesterone 3,20-bisethylene ketal; 9a-fluoro-A -pregnadiene-B,11,20-trione 3,20-bis-ethylene ketal; 9a-fiu0rO-prednisOne 3,20-bisethylene ketal; and 9a-fluoro-A F-pregnadicne-Z1-ol-3,ll, 20-trione 3,20-bis-ethyle'neketal'for the steroid reactants in the examples, one of the following, respectively, is obtained: 9a-methyl-1l-dehydrocorticosterone '3,20-bisethylene ketal; 9u-methyl-ll-keto-17a-hydroxyprogesterone 3,20-bis-ethylene ketal; 9q-methyl-A -pregnadiene- 3,11,20-trione 3,20-bis-ethylene ketal; 9a-methylprednisone 3,20-bis-ethylene ketal; and 9u-methyl-A -pregnadiene-21-ol-3,11,20-trione 3,20-bis-ethylene ketal. 7'

EXAMPLE 6 2.84; (no carbonyl bands) 9oc-methyl-1I-ketoprogesterone (IV) A solution of 60 mg. of 9u-methyl-1l-ketoprogesterone-3,20-bis-ethylene ketal in 10 ml. of methanol and l vml. of 8% sulfuric acid is heated under reflux for 4 hours. The reaction mixture is diluted with water and the steroids extracted with chloroform, the chloroform extract then being washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. Crystallization from acetone-hexane yields about 31 mg. of 9m.- methyl-1l-ketoprogesterone, having melting point about I EXAMPLE7 9cz-methylcor tis0ne (VI) A solution of mg. of 9a-methylcortisone-3,ZO-bisethylene ketal in 25 ml. of methanol and 1.84 ml. of 8% sulfuric acid is refluxed for 2% hours. Water is added and the reaction mixture neutralized with dilute sodium bicarbonate solution. After evaporation of the metha- .nol in vacuo the residual suspension is extracted with ethyl acetate and the ethyl acetate extract dried over sodium sulfate. Evaporation ofthe solvent in vacuo within the purview of this invention can be hydrolyzed to the free 3,20-diketone derivatives.

' I EXAMPLE 8 Qa-methylcortisdne 21 -acetate A solution of 18 mg. of 9a-methylcortisone in 1 ml. pyridine and 0.3 mliof acetic anhydride is allowed to stand at room temperature for .18 hours. After evaporation of the reagents in vacuo a crystalline residue remains which is recrystallized from acetone-hexane. Pure 90:- methylcortisone acetate has the following properties: M.P. about 258-260 (dec.); [a] +236 (c. 0.75 in chlf.);

M11; 239 m (e=l.7,100); hm? 3.01, 5.70, 5.78, 5.84, 6.01-6.05, 6.22;;

EXAMPLE v9 JQuQmEIhyMIfl-hydroxyprogesteron 3,20-bis-ethylene ketal Vll 7 solution of 9a-methyl-l1-ketoprogesterone-3,20-bisethylene ketal .in 100 ml. of freshly dried tetrahydrofuran is refluxed with 1.1 g. of lithium aluminum hydride for 18 hours. The reaction mixture is decomposed by the addition of ice and then a saturated sodium sulfate solution is added until the aluminum salts are formed into a slurry. The clear ether solution 'is' decanted olf and the residue is washed twice with chloroform. The combined organic extracts are dried over sodium sulfate and then evaporated to dryness in vacuo. The residue (about 425 mg; M.P. about 187-190") is dissolved in 50 ml.

of benzene and absorbed on 12g. of alumina. Elution with benzene and with chloroform:benzene 1:1) followed byerystallization from chloroform-methanol gives 337 mg. of the llB-hydroxy compound (VII) having M.P. about 194-196"; [11] +439 (c. 0.97 in CHCl hgg'ij 2.86

AnaIysis.-Calcd. $050, 11, 0 (432.58): C, 72.19;

.H, 9.32. Found: C, 71.68; H, 9.34.

EX MP a-methylhydrocortisone 3,20-bis-ethylene ketal (VIII) A solution of 4 g. of 9a-methylcortisone 3,20-bisethylene ketal in 267 ml. of pure tetrahydrofuran is refluxed with '2 grams of lithium aluminum hydride for 4 hours. After cooling excess lithium aluminum hydride is destroyed by the addition of acetone and after the addition of a saturated sodium sulfate solution the reaction mixture is extracted with chloroform. The chloroform solution is Washed with water, dried over sodium .sulfate'and concentrated to dryness in vacuo.

EXAMPLE 1 1 9a-methyl-1 1 fi-hydroxyprogesterone IX) A solution of 9a-methyl-11fi-hydroxyprogesterone-3,20- bis-ethylene ketal (315 mg.) in 25 ml. of methanol and 2.5 ml. of 8% sulfuric acid is heated under reflux for one hour. Upon dilution with water, about 207 mg. of 90amethyl-.1lfl-hydroxyprogesterone is precipitated with melting point about 228-231". Crystallization from chloroform-methanol gives. an analytical sample of 9c:- methyl-11 S-hydroxyprogesterone melting about 243-244"; [eth l-246 (c. 1.06 in CHCl 243 my (16,20 mgg fl 2.82, 2.92, 5.86, 5.91, 5.99,

max.

Analysis.-Calcd. for C I-1 0 (344.48): C, 76.70; H, 9.36. Found: C, 76.28; H, 9.14.

EXAMPLE 12 9a-methylhydrocortison (X) The crude reduction product (4 g.) obtained in Example 10 containing methylhydrocortisone 3,20 bisethylene ketal is dissolved in 655 ml. of methanol and 22.2 ml. of 8% sulfuric acid. The resulting mixture is refluxed for 94 of an hour, neutralized with dilute sodium bicarbonate and after the addition of water, the methanol is evaporated in vacuo. The residual suspension is extracted with ethyl acetate, the ethyl acetate extract washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residual crystalline material is first recrystallized from acetone-hexane and finally from 95% alcohol. There is obtained about 240 mg. of 9ix-methylhydrocortisone of the following properties: M.P. about 258-262 (dec.); [a] +187 (c. 1.24 in 95% ethanol);

Analysis.-Calcd. for C I-1 0 (376.48): C, 70.18; H, 8.57. Found: C, 69.91; H, 8.50.

Fractional crystallization of the mother liquors furnishes 9a-methylcortisone, which possesses about twice the activity of cortisone acetate in the rat liver glycogen assay. 7

EXAMPLE 13 9a-methylhydrocortisone 21 -acetate A solution of 24.4 mg. of 9u-methylhydrocortisone in 0.5 ml. of pyridine and 0.25 ml. of acetic anhydride is allowed to stand at room temperature for 18 hours. Evaporation of the reagents in vacuo furnishes a crystalline residue which after recrystallization from acetone-hexane yields pure 9a-methylhydrocortisone acetate of the following properties: M.P. about .244-245; [a]+184 (c. 0.24 in chit);

71:51,, 243 mp .(e=17,800); hm" 2.80, 2.99, 5.72, 5.80, 6.05, 6.20 1

Analysis.Calcd. for C H O (418.51): C, 68.87; H, 8.19. Found: C, 68.89; H, 8.20.

EXAMPLE 14 9m-methyl-l I a-hydraxyprogesterone 3,20-bis-ethylene ketal (XI To a stirred solution of mg. of 9a-methyl-l1-ketoprogesterone 3,20-bis-ethylene ketal in 100 ml. of liquid ammonia and 3 ml. of methanol, is added 100 mg. of lithium in small pieces over 15 minutes. The liquid ammonia is allowed to evaporate at room temperature and the residue is triturated with 50 m1. of water. The precipitated solid (about 94 mg., M.P. about 180-185") is collected, washed with water and dried. Crystallization from acetone-hexane gives an analytical sample of the IIoz-hydroxy compound (XI) having M.P. about 1 90-- M1347" (c. 1.03 in CHCI3);

Analysis.--Calcd. for C H O (432.58): C, 72.19; H, 9.32. Found: C, 72.49; H, 9.14.

EXAMPLE l5 9a -methyl-1 I -epihydrc0rtisone 3,20-bis-ethylene ketal (XII) To a solution of 200 mg. of 9u-methylcortisone-3,20- bis-ethylene ketal in 7 ml. of methanol and 40 ml. of liquid ammonia is added over a ten minute period at .60; 160 mg. of finely out lithium. The reaction is allowed to proceed without external cooling until most of the ammonia has evaporated (ca. one hour). Water and chloroform is then added and the chloroform extract washed several times with water until neutral. The chloroform solution is dried over sodium sulfate and evaporated to dryness in vacuo. The residue (about 230 mg.) after recrystallization from acetone gives pure 9a-methyl- 11-epihydrocortisone-3,ZO-bis-ethylene ketal of the following properties: M.P. about 274-276; [oc] -44 (c. 0.56 in chlf.);

k212i? 2.80, 2.87, 2.95 (inflection) Analysis.--Calcd. for C H O (464.58): C, 67.21;

H, 8.68. Found: C, 67.19; H, 8.66.

' EXAMPLE 16 9a-m ethyl-1 1 a-hydroxyprogesterone (XIII) A solution of 250 mg. of 9a-methyl-1lot-hydroxyprogesterone 3,20-bis-ethylene ketal in 10 ml. of methanol and 1 ml. of 8% sulfuric acid is heated under reflux for 1 hour. The mixture is then diluted with water, the precipi- '10 EXAMPLE 19 9a-methyl-1la-hydroxyprogesterone 1 I a-mesylate A solution of 93 mg. of 9a-methyl-11e-hydroxyprogesterone in 1 ml. of pyridine and 0.1 of mesyl chloride is allowed to stand at 0 for 18 hours. The mixture is then diluted with water and the precipitated solid collected and washed well with water. The resulting lla-mesylate (about 106 mg.) has a melting point about 203205' (dec.);

max. EXAMPLE 20 9a-methyl-1I-epihydrocortisone 11a,2I- a'iacetate (XVI) N513; 241 m (e=l6,300); 6.06, 6.20

Analysis.-Calcd. fOI (32 1-13507 C, H, 7.88. Found: C, 67.73; H, 7.91.

The invention may be otherwise variously embodied within the scope of the appended claims.

What is claimed is:

l. A compound selected from the group consisting of max.

steroids of the general formulae tated solid (about 180 mg., M.P. about 20l203) collected and crystallized from acetone-hexane to give the lla-hydroxy compound having M.P. about 205207; [a] +l93 (c. 1.08 in CHCI max.

Analysis.-.Calcd. for C H O (342.46): C, 77.15; H, 8.83. Found: C, 76.51; H, 9.18.

EXAMPLE 17 9a-methyl-1I-epihydrocortisone (XIV) drocortisone of the following properties: M.P. about 245-246"; [a] +140 (c. 0.56 in 95% ethanol);

A213, 243 m (e=15,800); x23 2.89, 5.85, 6.02, 6.22 1

Analysis.Calcd. for C H O (376.48): C, 70.18; H, 8.57. Found: C, 70.11; H, 8.51.

EXAMPLE 18 Qa-methyl-II u-hydroxyprogesterone 11 a-acetate (XV) A solution of 15 mg. of 9a-methyl-1la-hydroxyprogesterone in 0.5 ml. pyridine and 0.15 ml. of acetic anhydride is allowed to stand at room temperature for 16 hours. Dilution with ice-water followed by crystallization from acetone-hexane yields a sample of the Ila-acetate (about 9 mg.) having M.P. about 260-262"; [oc] +194 (c. 0.83 in CHCl wherein R is hydrogen, R is selected from the group consisting of a-hydroxy, a-acyloxy, and B-hydroxy, and together R and R is keto, R" is lower alkyl, Y is selected from the group consisting of hydrogen, hydroxy, and acyloxy, and Z is selected from the group consisting of hydrogen and oc-hYdl'OXY.

. 9a-methyl-ll-ketoprogesterone.

. 9a-methyl-ll-hydroxyprogesterone.

. 9a-methyl-l l fi-hydroxyprogesterone.

9a-methylcortisone.

. 9a-methyl-A -pregnene-11,17a-diol-3,20-dione.

. 9a-methylhydrocortisone.

. 9a(lower alkyl)-cortisone 3,20-diketal.

. 9a-methylcortisone 3,20-bis-ethylene ketal.

10. A process for preparing a 3,20-diketal of a (lower alkyl)-ll-ketoprogesterone oxygenated in at least one of the positions and 21, which comprises interacting the corresponding 3,20-diketal 9a-fluoro-ll-ketoprogesterone derivative with a reagent selected from the group consisting of a lower alkyl magnesium halide and 1 1 lithium lower alkyl, and recovering the 9a-lower alkyl steroid formed. I 7 r r 11. The process of claim IO-Wherein the steroid reactant is 9a-fluorocortis'one 3,20-bis-ethylene ketal.

12. A process for preparing a 3,20-diketal of 9a(1ower alkyD-ll-ketoprogesterone, which comprises interacting the corresponding 3,20-diketal of 9a-fluoro-11-ketoprogesterone with a lower alkyl magnesium halide and recovering the 9u-lo'we'r alkyl steroid formed.

13. A process for preparing a 3,20-diketal of a 904- methyl-ll-ketoprogesterone oxygenated in at least one of the positions 170: and 21, which comprises interacting the corresponding 3,20-diketal 9a-fluoro-ll-ketoprogesterone derivative with methyl magnesium bromide, and recovering the 9a-mcthylsteroid formed.

14. A process for preparing a 3,20-diketal of a 91':- methyl-ll-ketoprogesterone oxygenated in at least one of the positions 170: and 21, which comprises interacting the corresponding 3,20-diketal 9a-fiuoro-1l-ketoprogesterone derivative with lithium methyl, and recovering the 9a-methyl steroid formed.

15. A process for preparing a 3,20-diketal of 9u-methytll-ketoprogesterone, which comprises interacting the corresponding 3,20-diketa1 of 9a-fluoro-1l-ketoprogesterone 12 with methyl magnesium bromide, and recovering the 9c:- methyl steroid formed; I

16. A compound of the formula? wherein R is selected from the group consisting of lS-hydroxy and keto.

References Cited in the file of this patent UNITED STATES PATENTS 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF STEROIDS OF THE GENERAL FORMULAE 